Sustained-releasing methods of highly water-soluble medicinally active ingredients may roughly be classified into the following two types.
The first sustained-releasing method is by forming a matrix (JP-B 60-56122). According to this publication, the sustained-release was attained by the method wherein a water-soluble medicinally ingredient was granulated with hydrophobic substance to form a matrix. However, the control of release over 4 hours or longer is not described in this publication.
The second sustained-releasing method is by film coating (JP-A 63-27424). In this publication, the preparation to be coated with a binder or a film basis by using an organic solvent (the organic solvent method) was described to enable zero-order release over 10 hours or longer.
Though it is easy to control the release by the organic solvent method, its practical application is restricted due to environmental pollution, the remains of organic solvents in the preparation, maintenance of safety, and the like. Therefore, the methods of coating with an aqueous dispersion for sustained-release polymer by using water as a solvent and of coating only with heated and melted wax have recently been attempted.
As an aqueous dispersion for sustained-release polymer, ethylcellulose latex (Aquacoat (trade name), FMC), ethyl acrylate-methyl methacrylate copolymer (Eudragit NE 30D (trade name), Rohm Pharma), aminoalkyl methacrylate (Eudragit RS 30D (trade name), Rohm Pharma), and the like have been developed. However, it is difficult to control the release of highly water-soluble medicinally active ingredients over a long time even by using them. If the ingredient is coated with a very thick controlling layer, zero-order release cannot be achieved. The reasons in the method of controlling the release only with these sustained-release films are exemplified as follows; inconstant crystalinity of formed films, existence of micropores, susceptible to the surface construction of the material to be coated, gradual change of the ability of the releasing control, and the like.
In the method of coating only with heated and melted wax without using any organic solvent (JP-A 5-309314), the control of the initial period release and the sustained-release time are not satisfactory, and the control of release over a long time is difficult by this method.